Myeloid-Derived Suppressor Cells (MDSC) expressing Arginase (ARG) 1 are potent inhibitors of T cell function in cancer. MDSC deplete L-Arginine (L-Arg) in serum and the tumor microenvironment, severely impairing anti- tumor responses. Work done in the preceding five years identified the mechanisms by which MDSC deplete L- Arg and has started to identify the molecular mechanisms by which L-Arg depletion causes T cell anergy. We found that MDSC expressing ARG 1 infiltrate tumors and deplete L-Arg by rapid incorporation through CAT transporters. This L-Arg-depleted environment causes a T cell cycle arrest by inhibiting cyclin D3 and cdk4 (but not cyclin D2 or cdk6), inhibits the production of IFNg (but not IL2), and blocks the expression of the T cell receptor z chain (CD3z), severely impairing T cell function. Inhibition of ARG 1 re-establishes proliferation, IFNg production, and CD3z expression, and triggers an anti-tumor response. These mechanisms were found in mice and patients with cancer. Our results therefore suggest that L-Arg depletion triggers the selective inhibition of specific genes important for effector functions of T cells, and not a generalized decrease in protein synthesis from nutrient starvation. The data also suggest that this phenomenon is caused by the activation of a checkpoint that mediates the inhibition of these effector mechanisms. Therefore, blocking this checkpoint may make T cells resistant to the anergizing/tolerizing effect of MDSC. The proposed research will identify the molecular mechanisms triggered by L-Arg depletion that inhibit the expression of genes and proteins necessary for T cell effector functions. We will demonstrate the importance of these mechanisms in tumor- bearing mice and cancer patients, and will design and test novel therapeutic approaches that combine the inhibition of MDSC with the protection of T cells from the tolerizing tumor microenvironment.